Glial inwardly rectifying potassium channel 4.1 regulates secretion of BDNF and GDNF via ERK1/2 MAP kinases in trigeminal neuropathic pain.

Satellite glial cells (SGCs) in trigeminal ganglion (TG) are pivotal in the pathogenesis of trigeminal neuropathic pain (TNP). While astrocytic Kir4.1 and its potential downstream neurotrophic factors recently emerge as therapeutic targets for depression and pain, the specific role of Kir4.1 in SGCs related to TNP, along with underlying moleculars and cellular mechanisms, remains inadequately characterized. This study employed the chronic constriction injury of infraorbital nerve (CCI-ION) model to induce TNP, manifesting as orofacial mechanical hypersensitivity and activation of SGCs marked by GFAP expression. Kir4.1 was specifically expressed in SGCs and was downregulated following CCI-ION. To elucidate its role, tamoxifen or AAV2/8 targeting Kir4.1 was administered to wild-type and Kir4.1f/f mice for conditional knockdown (CKD) or overexpression. Both global and SGC-specific CKD of Kir4.1 induced mechanical hypersensitivity and increased GFAP, BDNF, and GDNF expression. Conversely, SGC-specific overexpression of Kir4.1 mitigated CCI-ION-induced hypersensitivity and the upregulation of GFAP, BDNF, and GDNF. Additionally, Kir4.1 knockdown via siRNA in cultured SGCs activated ERK1/2 phosphorylation and elevated BDNF and GDNF levels. Furthermore, ERK1/2 inhibitor U0126 reversed these effects. Thus, BDNF and GDNF serve as critical downstream factors of Kir4.1 in SGCs and are regulated by ERK1/2 MAP kinases, presenting potential therapeutic targets for TNP.